Substituted-i-adamantylmethyl
penicillins



United States Patent Matter enclosed in heavy brackets appears in theoriginal patent but forms no part of this reissue specification; matterprinted in italics indicates the additions made by reissue.

ABSTRACT OF THE DISCLOSURE Compounds having the following formula aredisclosed:

Y:a-methyl-l-adamantylmethyl 0r 3 isopropyl I adamantyl and X :hydrogento a non-toxic cation. These compounds find use for treatment ofbacterial diseases.

This invention relates to synthetic penicillins having [thelradamantylmethyl] certain adamantyl-containing side chains.

The [l-adamantylmethyl] penicillins Within the scope of this inventionare represented by the following formula:

where R and R are hydrogen or methyl;

S CHI i where Y is a-methyl-l-admantylmethyl or 3-isopr0pyl-I-adamantyl; and X is hydrogen or a non-toxic cation.

The compounds of Formula 1 are synthetic penicillins. Riegels IndustrialChemistry," Editor James A. Kent, Reinhold Publishing Corporation, NewYork, N.Y., 1962, p. 204, discusses the importance of syntheticpenicillins.

Economical methods have recently been found for removing thephenylacetyl side chain from penicillin G, leaving intact the nucleus,o-aminopenicillanic acid. A large number of synthetic penicillins" havebeen made by chemically coupling new side chains in the hopes ofaltering the range of therapeutic usefulness of the fundamental unit.Such improvements include resistance to penicillinase (an enzyme foundin penicillin-resistant Staphylococci) which inactivates the compound byopening the B-lactam ring. Others include enhanced activity againstgram-negative bacteria.

We have found that the use of [an adamantylmethyl] certainadamantyl-containing side chains [having one or two methyl groups on themethyl carbon or no sub- Re. 26,705 Reissued Nov. 4, 1969 "ice stitutionon the methyl carbon] gives synthetic penicillins which exhibit anunexpected improvement in decreased acid-sensitivity and greaterresistance to penicillinase than is found in known syntheticpenicillins. Particularly, preferred compounds of the invention due totheir outstanding stability are a-meIhyl-l-adamantylmethyl pencillin and3-isopropyl-I-adamantyl penicillin [those in which one or both hydrogensof the adamantylmethyl side chain are substituted with methyl groups,namely, e-methyl-l-adamantylmethyl penicillin anda,a-dimethyll-adamantylmethyl penicillin].

This invention embraces the non-toxic salts of the basic penicillinstructure of Formula 1 when X is hydrogen. Forming the salt enhances theusefulness of the basic penicillin structure by giving improvedwater-solubility and by improving acid stability due to the alkalinecharacter of the salt. The two most preferred salts are the sodium andpotassium salts. Representative of these salts are:

Sodium l-adamantylmethyl penicillin Potasium l-adamantylmethylpenicillin Sodium tx-methyl-l-adamantylmethyl penicillin Potassiuma-methyl-ladamantylmethyl penicillin [Sodiumu,a-dimethyl-l-adamantylmethyl penicillin] [Potasiuma,a-dimethyl-l-adamantylmethyl penicillin] Sodium3-isopropyl-l-adamanzyl penicillin Potassium 3t-is0pr0pyl-1adamantylpenicillin However, it is to be understood that other salts of the basicpencillin structure of the invention which utilize a non-toxic cationare also included within the compound scope of the invention.Illustrative of such other salts are the salts with organic bases suchas procaine, chloroprocaine, hydrabamine[N,N-bis-(dehydroabietyl)-ethylenediamine].

The penicillins of this invention are prepared by the reaction of theappropriate acid chloride with -aminopenicillanic acid (commerciallyavailable) in chloroform containing triethylamine at 0 to 25 C. Afterreaction. the tricthylamine is removed by treatment with dilute acid,and the penicillin is extracted into aqueous sodium bicarbonate. Removalof the water at low temperature and pressure gives the sodiuml-adamantylmethyl penicillin. This may be purified by recrystallizationin some cases, and in many cases the product is sufiiciently pure to beused directly. Use of aqueous potassium bicarbonate gives the potassiumsalts. Neutralization with acid gives the acid forms. These may betreated with an organic base in aqueous solution or organic solvents toyield the organic base salts.

The preparation of the three carboxylic acid intermediates[l-adamantylacetic acids and their acid chlorides] is discussed fully inthe following specific examples of the synthesis of the compounds ofthis invention.

EXAMPLE 1 Sodium l-adamantylmethyl penicillin A mixture of 0.10 mole ofl-adamantaneacetic acid (H. Stetter, M. Schwarz and A. Hirschorn, Ber.,92, 1629 (1959)) and 60 ml. of thionyl chloride is refluxed for 2.5hours. The excess thionyl chloride is removed by vacuum concentrationand the residue is vacuum-distilled to give l-adamantaneacetyl chloride.

A solution of 10.88 g. (0.0492 mole) of 6-amino penicillanic acid and0.0984 mole of triethylamine in 66 ml. of chloroform in a 300-ml.round-bottom flask fitted with a stirrer, a thermometer and a droppingfunnel is stirred and cooled to 0 C., using an ice-salt bath. Withstirring, a solution of 0.492 mole of l-adamantaneaoetyl chloride in 66ml. of chloroform is added dropwise at such a rate that the temperaturedoes not rise above C. This takes about 15 minutes. The cooling bath isremoved and the mixture is stirred for two hours, gradually warming toroom temperature during this time. Then, it is again cooled to 0 C. andtransferred to a separatory funnel. It is extracted with 49 ml. of cold1 N hydrochloric acid. The chloroform layer is then extracted with 49ml. of 1.00 N sodium bicarbonate. The sodium bicarbonate extract isconcentrated in a vacuum at a temperature below 35 C. to yield sodiuml-adamantylmethyl penicillin as the residue. If, after extracting withthe 1 N hydrochloric acid, the chloroform layer is concentrated in avacuum at low temperature, the residue is mainly l-adamantylmethylpenicillin.

EXAMPLE 2 Sodium a-methyl-l-adamantylmethyl penicillin A mixture of 0.10mole of l-adamantyl methyl ketone (H. Stetter and P. Goebel, Ber., 95,1039 (1962)); H. Stetter and E. Rauscher, Ber., 93, 2054 (1060) and 75ml. of ether is added dropwise to a suspension of 0.05 mole of lithiumaluminum hydride in 150 ml. of ether. The reaction mixture is refluxedfor an hour after addition is complete. Then, the excess lithiumaluminum hydride is decomposed with saturated aqueous sodium sulfate,the solids are removed by filtration, and the filtrate isvacuumconcentrated to remove ether and water. The residue isa-methyl-ladamantanemethanol.

A mixture of 0.32 mole of a-methyl-l-adamantanemethanol, 3 ml. ofconcentrated hydrochloric acid, 15 ml. of water, 5 g. of nickel chloridehexahydrate and 17 g. of nickel carbonyl is placed in a glass-linedautoclave. The autoclave is pressured to 900 p.s.i.g. with carbonmonoxide and then heated at 275-300 C. for 24 hours. It is then cooled,vented, and its contents are extracted with ether. The ether extract isevaporated and the residue is neutralized with sodium hydroxidesolution. This mixture is extracted with ether, and the ether extract isdiscarded. The aqueous layer is made strongly acidic with concentratedhydrochloric acid and extracted with ether. The ether extract is driedwith anhydrous magnesium sulfate, and then evaporated to yield a residueof u-methyl-ladamantaneacetic acid.

A mixture of 0.10 mole of a-methyl-l-adamantaneacetic acid and 65 ml. ofthionyl chloride is refluxed for 2 hours. Then, the excess thionylchloride is removed by vacuum distillation, and the residue isvacuum-distilled to yield a-methyl-l-adamantaneacetyl chloride.

The procedure of Example 1 is repeated, using 0.0492 mole ofa-methyl-l-adamantaneacetyl chloride in place of the 0.0492 mole ofl-adamantaneacetyl chloride. Sodium a-methyl-l-adarnantylmethylpenicillin is obtained. If 49 ml. of 1.00 N potassium bicarbonate issubstituted for the 49 ml. of 1.00 N sodium bicarbonate, potassiumntmethyl-l-adamantylmethyl penicillin is obtained.

EXAMPLE 3 [Sodium m,a-dimethyl-l-adamantylmethyl penicillin] Sodium3-is0pr0pyI-1-aa'amantyl penicillin To a solution of 31.5 g. ofl-adamantoyl chloride in 500 ml. of anhydrous ether under a nitrogenatmosphere is added, dropwise 150 ml. of commercial 3 M methyl magnesiumbromide at a rate which maintains a gentle reflux. The reaction mixtureis heated for 1 hour after the addition, then cooled. To decompose themetal complex, 300 ml. of saturated ammonium chloride is added. Theether layer is separated and the aqueous layer is extracted with 100 ml.of chloroform. This extract is combined with the ether layer, and themixture is dried with anhydrous magnesium sulfate andvacuum-concentrated to dryness at 35 C. The residue is steam-distilleduntil the distillate is no longer milky, about 3 liters of distillatebeing collected. On cooling, the steam distillate crystallizes. Thesolids are filtered and dried to yield 26.9 g. of wclimethyl-hdamantanemethanOL M.P. 7780 C.

A suspension of 25 g. of m,a-dimethyl-l-adamantanemethanol in 100 ml. of98% formic acid is added to a mixture of 600 ml. of concentratedsulfuric acid and 400 ml. of carbon tetrachloride. One hour after theaddition is complete, the reaction mixture is poured on 1000 g. of ice.The organic layer is separated, and the aqueous layer is washed withcarbon tetrachloride. The carbon tetrachloride extract and the organiclayer are combined and extracted with 10% sodium hydroxide solution. Theaqueous layer is separated and then made strongly acidic withconcentrated hydrochloric acid. This mixture is extracted with ether,and the ether extract is dried with anhydrous magnesium sulfate andconcentrated in a vacuum. The residue is a syrup, which crystallizes oncooling to yield 14.3 g. of [a,m-dimethyl-l-adamantaneacetic acid]3-isopropyl-I-adamanrylcarboxylic acid melting at 7S C.

A mixture of 14 g. of [a,u-dimethyl-l-adamantaneacetic acid]3-isopropyl-I-aaamantyl carboxyl'ic acid and 60 ml. of thionyl chlorideis refluxed for 3 hours. The excess thionyl chloride is removed bydistillation and the residue is vacuum-distilled to yield[(1,0t-(ll1'll8lhYl-l-3dflmantaneacetyl chloride]3-isopr0pyl-1-adamantyl carboxylic acid chloride.

The procedure of Example 1 is repeated, using 0.0492 mole of[a,ot-dimethyl-l-adamantaneacetyl chloride] 3- isopropyl-l-adamantylcarboxylic acid chloride in place of the 0.0492 mole ofladamantaneacetyl chloride.

Sodium [a,a-dimethyl-l-adamantylmethyl] 3-isopr0-pyl- I-adamamylpenicillin is obtained.

The compounds of the present invention exhibit the utility known forsynthetic penicillins generally and, therefore, find use for treatmentof bacterial diseases. In particular, these compounds show activityagainst Pneumococci, streptococci, and Staphylococci. In addition, thesecompounds are useful in the treatment of gram-negative organisms and canbe used against organisms usually resistant to nonsynthetic penicillins.

The compounds of the invention can be administered for the treatment ofbacterial diseases by any means that effects contact of the compoundwith the organism to be controlled. Preferably administration isaccomplished orally or intramuscularly.

The dosage administered will be dependent on the organism being treatedas well as the age, health, and weight of the recipient, the nature ofthe effect desired, and the kind of concurrent treatment, if any.Generally, however, for an adult the dosage will be in the range ofabout 1-6 grams per day. For a child, the dosage usually will be in therange of about 40-120 milligrams per kilogram of body weight per day.

The dosage form for administration of the compounds, of course, willvary depending on the route of administration employed. For oraladministration, these compounds can be employed in useful compositionsin such dosage forms as tablets, capsules, powder packets, liquidsolutions, liquid suspensions, or elixirs. In such compositions, theactive compound will ordinarily be present in an amount of at least 0.5%by weight based on the total weight of the composition and not more thanby weight. For intramuscular administration, these active compounds canbe employed in sterile solutions, preferably a saline solution. Thesesolutions will ordinarily contain from about 0.5% to 25% and preferablyabout 1 to 10% by weight of the active compound.

Besides the active compound of the invention, these compositions used asdosage forms will contain solid or liquid non-toxic pharmaceuticalcarriers for the active compound. Suitable pharmaceutical carriers aredescribed in Remingtons Practice of Pharmacy by E. W. Martin and E. F.Cook, a well-known reference text in this field.

The disclosure herein should not be taken as a recommendation to use thedisclosed invention in any way without full compliance with US. Food andDing Laws and other laws which cover regulations which may beapplicable.

where:

R is selected from the group consisting of hydrogen and methyl; and

X is selected from the group consisting of hydrogen and a non-toxiccation] 2. a-methyl-l-adamantylmethyl penicillin. [3.a,u-dimethyl-1-adan1antylmethyl pencillin].

[4. Sodium a,0z dimethyl-l-adamantylmethyl pcncil- 25 lin.]

5. A compound selected from tlze group consisting of compounds of theformula where Y is selected from the group consisting ofamethyl-I-adamantylmethyl and 3-isopropyl-1adamantyl; and X is selectedfrom the group consisting of hydrogen and a non-toxic cation.

6. 3-is0propyl-1-adamantyl penicillin.

7. Sodium 3-isopropyl-1-adamantyl penicillin.

References Cited The following references, cited by the Examiner, are ofrecord in the patented file of this patent or the original patent.

UNITED STATES PATENTS 3,252,973 5/1966 Flynn 260243 NICHOLAS S. RIZZ'O,Primary Examiner US. Cl. X.R. 424-271

